Pii: s0304-3940(02)00027-7

Effects of electroacupuncture on the mechanical allodynia in the rat Byung Gil Hwanga, Byung-Il Mina,*, Ji Hoon Kima, Heung Sik Nab, Dong Suk Parkc aDepartment of East–West Medicine, Graduate School, Kyung Hee University, Seoul, South Korea bDepartment of Physiology, College of Medicine, Korea University, Seoul, South Korea cDepartment of Acupuncture and Moxibustion, College of Oriental Medicine, Kyung Hee University, Seoul, South Korea Received 1 November 2001; received in revised form 26 December 2001; accepted 27 December 2001 The analgesic effects of acupuncture on the mechanical allodynia in the rat model of neuropathic pain have not yet been studied. The aim of the present study is: first, to determine if electroacupuncture (EA) or morphine attenuates themechanical allodynia; and secondly, to examine if the EA effect may be mediated by endogenous opioids. To produceneuropathic pain, the right superior caudal trunk was resected between the S3 and S4 spinal nerves. Twenty-one daysafter the neuropathic surgery, low frequency EA stimulation (2 Hz, 0.3 ms, 0.07 mA) delivered to Houxi (S13) for 30 minrelieved significantly the signs of mechanical allodynia. Intraperitoneal (i.p.) morphine (0.5 or 1.5 mg/kg) also relieved thesigns of mechanical allodynia in a dose-dependent manner. In addition, the antiallodynic effect of Houxi EA was blockedby pretreatment with naloxone (2 mg/kg, i.p.). However, combined application of EA and morphine did not show anobvious synergistic effect. These results suggest that low frequency EA or morphine can relieve the mechanical allodyniasigns and the EA effect can be mediated by endogenous opioid systems. q 2002 Elsevier Science Ireland Ltd. All rightsreserved.
Keywords: Electroacupuncture; Opioid; Naloxone; Neuropathic pain; Mechanical allodynia; Morphine Partial peripheral nerve injury sometimes leads to neuro- is controversial whether morphine relieves the neuropathic pathic pain. This type of pain is characterized by sponta- pain. Thus, the present study aims to determine whether neous burning pain, hyperalgesia (an increased sensitivity to electroacupuncture (EA) or morphine can relieve mechan- painful stimuli), and allodynia (the perception of normally ical allodynia produced by peripheral nerve injury and, if innocuous stimuli as painful). Numerous studies have EA relieved the mechanical allodynia, to see whether EA attempted to find pathophysiological mechanisms or drug effects can be mediated by an endogenous opioid.
effects on this abnormal sensation in patients or animals [3].
Young adult male Sprague–Dawley rats (n ¼ 79; 200– Acupuncture analgesia for this pain condition has been 250 g) were housed in group cages (4–5 per cage) with studied regarding neuropathic pain of malignancy [4], water and food available ad libitum. The room was light/ HIV-related peripheral neuropathic pain [7,12] and diabetic dark (08:00–20:00 h light, 20:00–08:00 h dark) controlled neuropathy in patients [5] or hyperalgesia in a neuropathic and kept at 21–24 8C. Under sodium pentobarbital anesthe- sia (40 mg/kg, intraperitoneally (i.p.)), the right superior However, although it has been well known that acupunc- caudal trunk was exposed and transected at the level ture analgesic effects on nociceptive pain are mediated by between the S3 and S4 spinal nerves that innervate the rat endogenous opioids and other neurotransmitters in the tail as previously described by Na and his coworkers [9].
central nervous system [6], the mechanism of acupuncture Mechanical sensitivity was examined 1 day prior to the analgesia for neuropathic pain is uncertain. Furthermore, it neuropathic surgery, and 1, 4, 7, 14 and 21 days postopera-tively. As described previously [9], the mechanical allody-nia was assessed by normally innocuous stimulation of the * Corresponding author. Department of Physiology, College of tail with the von Frey hair (bending force, 19.6 mN, 2.0 g).
Medicine, Kyung Hee University, #1 Hoegi-Dong, Dongdae-moon-Gu, Seoul, 130-701, South Korea. Tel.: 182-2-961-0286; For proper application of stimuli with the von Frey hair and acupuncture, the rat was restrained in a plastic holder E-mail address: [email protected] (B.-I. Min).
0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 3 0 4 - 3 9 4 0 ( 0 2 ) 0 0 0 2 7 - 7 B.G. Hwang et al. / Neuroscience Letters 320 (2002) 49–52 dynia was mediated by an endogenous opioid system, nalox-one (Sigma; 2 mg/kg) was injected i.p. 20 min before theEA. In addition, to assess the effects of morphine or EA withmorphine on mechanical allodynia, morphine (Myeng MunPharmaceutical Co., South Korea; 0.5 and 1.5 mg/kg, i.p.)was injected 10 min before the EA.
Data are expressed as means ^ SEM. The significance of statistical differences were determined using Friedman’srank test followed by Dunnett’s post-hoc test in a groupand using the Mann–Whitney U-test between two groups.
P , 0:05 was considered significant.
Fig. 1. Schematic diagram of the apparatus for EA and behavioral The effects of H-EA or NA-EA on the mechanical allo- test on the mechanical allodynia in the rat model of neuropathic dynia are shown in Fig. 2. In the NA-EA group (Fig. 2; open circles), the values prior to and 15, 30, 45 and 75 min afterthe (5.3 £ 15 cm in diameter £ length) and the tail was laid on a 91.4 ^ 4.6, 94.3 ^ 2.9 and 97.1 ^ 1.8%, respectively. No plate. The mechanically sensitive area was first determined statistically significant difference between the values before by rubbing various areas of the tail with von Frey hair. The and after EA was detected (Friedman’s rank test). On the actual test was performed by gently poking the most sensi- other hand, in the H-EA group (Fig. 2; closed circles), the tive spot with the von Frey hair. An abrupt tail movement of values for response frequencies prior to and 15, 30, 45 and more than 0.5 cm was considered to be an abnormal 75 min after the beginning of EA were 97.1 ^ 1.8, response attributed to mechanical allodynia. The stimula- tion was repeated ten times at 10–20 s intervals for each respectively. The values at 15, 30 and 45 min after the animal on each testing time or day (Fig. 1). The degree of beginning of H-EA were all significantly lower than the response was expressed as a percentage of response value before EA (Dunnett’s post-hoc test after Friedman’s rank test) and the maximal relieving effect of H-EA wasshown at 30 min after the beginning of EA. These results indicate that the stimulation of acupoint, but not non- acupoint can relieve the signs of mechanical allodynia in Two weeks after the neuropathic surgery, the behavioral test was performed with von Frey hair, and rats displaying well- The results of naloxone pretreatment of the H-EA rats are developed behavioral signs of mechanical allodynia were shown in Fig. 3. Naloxone pretreatment (H-EA 1 Nx selected. These rats were restrained in special holders.
Each holder (5.3 £ 15 cm in diameter £ length) has a rectan-gular hole (7 £ 2.5, 8 £ 3 cm) on one side, a glass funnelinside to cover the rat’s head, and a small barrier was placedbetween the forelimbs of a rat. Rats were properly fitted inthese holders with their tails protruding outside, and theywere allowed to adapt to the environment for 30–90 min/dayfor 3–7 days. After the adaption period, a pair of stainlesssteel needles (interpolar distance, 3 mm) were inserted intothe Houxi acupoint (SI3), which is located laterally behindthe distal end of the 5th metacarpal bone of each rat. Thispoint has been used in clinical practice for pain relief [13].
This method for stimulating the acupoint located in theforelimb of a rat is somewhat similar to those previouslyused for mice [11]. To obtain the control data, a non-acupoint was selected in the abdominal area. Train-pulses(2 Hz, 0.3 ms pulse width, 0.07 mA, produced by Nihon Fig. 2. Effects of H-EA or NA-EA on the signs of mechanical allo- Kohden made in Japan) were delivered to the inserted dynia. Data were expressed as a percentage of the mean ^ SEM.
needles at both acupoint (H-EA) and non-acupoint (NA- Each group was given train-pulse (2 Hz, 0.3 ms duration, 0.07 EA) for 30 min, and the needles were removed immediately mA) for 30 min. The H-EA group (closed circles) shows the reduc- following the simulation. The behavioral test was performed tion of the tail response frequency following the beginning ofEA, whereas the NA-EA group (open circles) showed no prior to and 15, 30, 45 and 75 min after the beginning of EA.
changes. Asterisks indicate values significantly different from If EA had relieved the signs of mechanical allodynia, in the value before EA (P , 0:05, Dunnett’s post-hoc test after order to determine whether this effect on mechanical allo- B.G. Hwang et al. / Neuroscience Letters 320 (2002) 49–52 reduction of pain responses induced by manual acupunctureon hyperalgesia in neuropathic rats with a chronic constric-tion injury in the sciatic nerve [10]. Taken together, theantiallodynic effects of acupuncture on mechanical allody-nia may be mediated by endogenous opioids.
Although the efficacy of opioids in relieving neuropathic pain is a controversial issue [2], the present result agreeswith the results of Chung and Na [1] that mechanical allo-dynia in the SNL model was relieved by systemic morphinein a dose-dependent manner. However, H-EA 1 M (0.5 mg/kg), contrary to our expectation, did not induce a synergisticeffect on the antinociceptive effects of H-EA, although H-EA 1 M (1.5 mg/kg) induced slightly more antiallodyniceffects than H-EA. This phenomenon is similar to the resultsof Takeshige [14] that combined application of acupoint Fig. 3. Effects of naloxone pretreatment (arrow) on the antiallo-dynic effects of H-EA. Intraperitoneal injection of naloxone (Nx, 2mg/kg) reversed the antiallodynic effect of EA. SL, normal saline.
Asterisks indicate values significantly different from the valuebefore EA (P , 0:05, Dunnett’s post-hoc test after Friedman’srank test).
group) reversed the antiallodynic effect of H-EA, while H-EA 1 saline (H-EA 1 SL) did not show such changes.
These results suggest that the antiallodynic effect of H-EAcan be blocked by naloxone.
The effects of morphine (0.5 and 1.5 mg/kg) or H-EA with morphine (H-EA 1 M) on the signs of mechanical allodyniaare shown in Fig. 4A,B. In the 0.5 mg/kg morphine group(Fig. 4A; closed triangle), the value at 15 min after the injec-tion was slightly lower than the value before the injection,whereas the values at 15, 30, 45 and 75 min after the injectionin the 1.5 mg/kg morphine group (Fig. 4B; closed triangle)were significantly lower than the value before the injection(Dunnett’s post-hoc test after Friedman’s rank test).
However, in the H-EA 1 M groups (M (0.5 mg) or M (1.5mg); Fig. 4A,B), no statistically significant difference wasdetected between H-EA 1 M and H-EA 1 SL groups,except at 45 min following the beginning of EA in the H-EA 1 M (1.5 mg) group (Mann–Whitney U-test). Theseresults suggest that morphine relieves the signs of mechan-ical allodynia in a dose-dependent fashion. However,combined application of H-EA and morphine did not showan obvious synergistic effect.
The results of the present study demonstrate that low Fig. 4. The effects of morphine (0.5 or 1.5 mg/kg) or H-EA 1 M on frequency (2 Hz) H-EA or morphine can reduce the signs the signs of mechanical allodynia. A high dose (1.5 mg/kg (B), of mechanical allodynia, produced by partial injury of the closed triangles) of morphine more effectively relieves the signs nerves innervating the rat’s tail. This antiallodynic effect of of mechanical allodynia than a low dose (0.5 mg/kg (A), closedtriangles) of morphine. Asterisks indicate values significantly EA is in line with the findings of Leem et al. [8], that different from the value before the intraperitoneal injection of morphine in M (0.5 mg) and M (1.5 mg) groups (P , 0:05, reduced the enhanced mechanical responsiveness of the Dunnett’s post-hoc test after Friedman’s rank test). The antiallo- spinal neurons in a rat model of peripheral neuropathy dynic effects of H-EA 1 M groups (0.5 or 1.5 mg) were not differ- induced by a tight ligation of L5–6 spinal nerves (SNL).
ent from those of H-EA 1 SL (normal saline) groups, except at 45min following the beginning of EA in the H-EA 1 M (1.5 mg) In addition, in the present study, the antiallodynic effects group. The asterisk indicates a significant difference between of EA were blocked when naloxone pretreatment was used.
the H-EA 1 M (1.5 mg) group and the H-EA 1 SL group Consistent with the present results, naloxone prevented B.G. Hwang et al. / Neuroscience Letters 320 (2002) 49–52 stimulation and morphine (0.5 mg/kg, i.p.) did not show a related peripheral neuropathic pain, J. Am. Med. Assoc., synergistic effect on nociceptive pain in rats.
281(14) (1999) 1270 (Discussion pp. 1271–1272).
[8] Leem, J.W., Park, E.S. and Paik, K.S., Electrophysiological The results of this study suggest that morphine can relieve evidence for the antinociceptive effect of transcutaneous the signs of mechanical allodynia and the relieving effects of electrical stimulation on mechanically evoked responsive- low frequency (2 Hz) H-EA on the mechanical allodynia ness of dorsal horn neurons in neuropathic rats, Neurosci.
can be mediated by endogenous opioids.
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[14] Takeshige, C., Nakamura, A., Asamoto, S. and Arai, T., Posi- [6] Han, J.S. and Trenius, L., Neurochemical basis acupuncture tive feedback action of pituitary b-endorphin on acupunc- analgesia, Annu. Rev. Pharmacol. Toxicol., 22 (1982) 193–220.
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